Nuclear receptors (NR) are family of DNA transcription factors found within cells that are involved in various transcriptional programs in the body. There are 48 kinds of nuclear receptors identified depending upon the ligands. In normal state, NRs exist in inactive forms forming homodimer or heterodimer complexes with corepressors. Endogenous ligands in response to external stimuli or exogenous ligands activate NRs inducing dissociation of corepressors and recruit coactivators which lead to the DNA response element and interaction between NRs and transcription factors, thereby regulating the expression of target genes (McKenna, N. J. et al. Mol. Endocrinol. 2009, 23: 740-746). And also, post translational modifications, such as acetylation, phosphorylation, ubiquitination, etc., play a critical role in regulating the activities of nuclear receptors.
Liver X receptor (LXR), one of the NRs activated by endogenous ligand oxysterol, is a transcription factor involved in the control of cholesterol homeostasis in the body. Oxysterols, oxidized forms of cholesterols, are produced by the cholesterols metabolism in the body (Lehmann, et al. J. Biol. Chem. 1997, 272(6):3137-3140). There are two isoforms of LXR: LXRα and LXRβ. The two isoforms share about 77% sequence homology in their ligand binding domains (LBD). The LXRα is predominantly expressed in the liver, while the LXRβ is expressed ubiquitously in the body (Willy, et al. Gene Dev. 1995, 9(9):1033-1045). LXR facilitates the excretion of cholesterols through reverse cholesterol transport (RCT) from the peripheries to the liver. In the RCT, two cholesterol transporters, i.e., the ABC-A1 (ATP-binding cassette transporter A1) and the ABC-G1 (ATP-binding cassette transporter G1) expressed in peripheral macrophages, play a crucial role. LXR ligands increase the expressions of ABC-A1/G1, thereby stimulating the RCT (J Clin Invest 2006, 116(3):607-614).
The overexpression of ABC-A1 in an experimental model of atherosclerosis (i.e., apoE-knockout mice) showed 66% reduction in atherosclerotic lesion formation in the blood vessel (Singaraja, et al. J Clin Invest 2002, 110(1):35-42). The knockout of LXRα gene results in abnormal control of cholesterol levels, which leads to liver damages along with increased LDL level, decreased HDL level, and decreased expressions of lipid-related genes in the blood vessel (Peet et al. Cell 1998, 93:693-704). The double knockout of LXRα/β exhibits decreased expressions of cholesterol transporters and increased lipid accumulation in macrophages, thereby facilitating atherogenesis, which mimics the symptoms of Tangier disease, a human genetic HDL deficiency (Tangirala et al. PNAS 2002, 99(18):11896-11901). And also, it has been reported that, when human peripheral blood monocytes (PBMC) were treated with synthetic LXR ligands, the expressions of ABC-A1 and ABC-G1 genes were rapidly increased (Diblasio-Smith et al. J Transl Med 2008, 6(59):1-15). It has been reported that, when a synthetic ligand was single administered to healthy participants followed by measuring the relationship between the blood concentration and the expressions of ABC-A1/G1, the expressions of ABC-A1/G1 were increased in a dose-proportional manner (Katz et al. J Clin pharmacol 2009, 49:643-649).
Therefore, a ligand capable of increasing the LXR transcriptional activity is expected to be useful for preventing or treating a dysfunction in cholesterol metabolism, including e.g., cholesterol gallstone, hyperlipidemia, or coronary atherosclerosis.